Novel compounds

ABSTRACT

Compounds of formula I, or a salt thereof or a hydrate thereof, as follows:  
                 
 
     wherein  
     X and Y are selected independently from hydrogen and aryl, which aryl is unsubstituted or substituted one or more times by hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, aryl, heterocyclyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, arylC 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkoxy or halo, which alkyl or alkoxy groups are unsubstituted or substituted one or more times by halo;  
     m and n are independently 0 to 3, provided that m and n are not both 0;  
     A represents a single bond or is —(CR pa  R pb ) p — wherein p is 1-3 and R pa  and R pb  are selected independently from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and halo, which alkyl or alkoxy groups are independently substituted one or more times by halo;  
     B represents a C 4-8  saturated or unsaturated ring, which ring is unsubstituted or substituted one or more times by C 1-6 alkyl, C 1-6 alkoxy, aryl, aryloxy, hydroxy, oxo, halo, amino, C 1-6 alkylamino, di(C 1-6  alkyl)amino, and C 1-6 alkylamido, which C 1-6 alkyl or C 1-6 alkoxy groups are unsubstituted or substituted one or more times by halo, which aryl group is unsubstituted or substituted one or more times by aryl, heterocyclyl, aryloxy, arylC 1-6 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, arylC 1-6 alkyl, hydroxy, C 1-6 alkenoxy, C 1-6 alkoxy, halo, or C 1-6 alkyl, which C 1-6 alkyl may be substituted one or more times by halo, and which aryl group is linked to said ring by a single bond or is benzo-condensed therewith are ligands of the ORL-1 receptor.

[0001] The present invention relates to certain novel compounds, toprocesses for preparing such compounds, to pharmaceutical compositionscontaining such compounds, and to the use of such compounds in medicine.

[0002] The ORL-1 receptor is found throughout the whole of the neuraxisand is known to be involved in the transmission of pain.

[0003] European Patent Application EP-A-0856514 (F. Hofmann-LaRoche A G)discloses 8-substituted-1,3,8-triaza-spiro[4.5]decan-4-one derivativesthat are agonists and/or antagonists of the ORL-1 receptor. Said ORL-1receptor is also known as the nociceptin/OFQ receptor.

[0004] Eur. J. Med. Chem. 1978;13:533-547 (Eirin et al.) discloses(±)-3-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalenefor use as a neuroleptic agent.

[0005] An. Real. Acad. Farm. 1989;55:461-469 (Santana et al.) discloses(±)-2-[(4-phenylpiperidin-1-yl)methyl]-1,2,3,4-tetrahydronaphthalene asan antidopaminergic agent.

[0006] U.S. Pat. No. 3,812,119 (Ciba-Geigy Corporation) disclosescertain dibenzocycloheptenes that have utility as antidepressants.

[0007] U.S. Pat. No. 4,022,791 (Pfizer Inc.) discloses certain2-aminomethyl-3,4-dihydronaphthalenes as analgesics.

[0008] J. Med. Chem. 1977;20(5):699-705 (Welch et al) discloses5,8-disubstituted 1-tetralones as analgesics and tranquillisers.

[0009] J. Med. Chem. 1978;21(3):257-263 (Welch et al) discloses certain5,8-disubstituted 2-aminomethyl-3,4-dihydronaphthalenes as analgesicsand tranquillisers.

[0010] International Application Publication Number WO 98/36749(Bristol-Myers Squibb) discloses certain tetralone derivatives asantiarrhythmic agents.

[0011] United Kingdom Patent Application GB2177084 (Imperial ChemicalIndustries PLC) discloses certain benzopyran derivatives as fungicides.

[0012] United Kingdom Patent Application GB2177085 (Imperial ChemicalIndustries PLC) discloses certain benzocycloalkylmethylamines asfungicides.

[0013] Co-pending International Application Publication Number WO99/06397 (Abbott Laboratories) discloses certain piperidine compoundsuseful as endothelin antagonists.

[0014] International Application Publication Number WO 98/02432 (TakedaChemical Industries Ltd) discloses certain phenylpiperidino compoundsuseful for the treatment of lower urinary tract infections.

[0015] International Application Publication Number WO 96/22977discloses certain piperidinyl derivatives for treating symptoms ofischaemic diseases and preventing cytotoxic calcium overload.

[0016] International Application Publication Number WO 97/23458(Cocensys Inc.) discloses certain tetrahydronaphthyl and piperidinederivatives as sub-type selective N-methyl-D-aspartame receptor ligands.

[0017] U.S. Pat. No. 5,436,255 (Pfizer Inc.) discloses certain3-piperidino-1-chromanol derivatives for blocking the NMDA receptorsite.

[0018] International Application Publication Number WO 95/00131(university of Virginia Commonwealth) discloses certain aminederivatives as useful in the treatment of CNS disorders.

[0019] European Patent Application EP 0 745 598 (Adir et Compagnie)discloses certain piperazine, piperidine, and tetrahydropyridinecompounds as ligands of the D₄ dopamine receptor.

[0020] European Patent Application EP 0 742 207 (Eisai Co. Ltd.)discloses certain cyclic amines as having acetylcholine esteraseactivity.

[0021] U.S. Pat. No. 5,215,989 (Merck & Co. Inc.) discloses certaindisubstituted piperazine and imidazole derivatives useful as Class IIIantiarrhythmic agents.

[0022] International Application Publication Number WO 93/00313(University of Virginia Commonwealth) discloses certain aminederivatives as selective sigma receptor binding agents.

[0023] European Patent Application EP 0 479 601 (Ajinomoto KK) disclosescertain piperidine derivatives as antiarrhythmic agents.

[0024] Japanese Patent Application JP 2169 569 (Eisai KK) disclosescertain cyclic amine derivatives for the treatment or prophylaxis ofe.g. senile dementia, cerebral apoplexy, and cerebral atherosclerosis.

[0025] It has now been found that certain nitrogen heterocycles areligands of the ORL-1 receptor, and therefore may be useful as ananalgesic in humans or animals for the treatment, for example, of acutepain; chronic neuropathic or inflammatory pain, including post herpeticneuralgia, neuralgia, diabetic neuropathy and post stroke pain;osteoarthritis/back pain; and painful pregnancy labour.

[0026] These compounds may also therefore be useful in the treatment orprophylaxis of eating disorders, such as anorexia and bulimia; anxietyand stress conditions; immune system diseases; cardiovascular systemdysfunctions; memory loss, cognitive disorders, motor impairment andneurodegeneration owing to Alzheimer's disease, senile dementia,Parkinson's disease or other neurodegenerative pathologies; stroke;epilepsy; altered diuresis and sodium excretion; syndrome ofinappropriate secretion of antidiuretic hormone (SIADH); adultrespiratory distress syndrome (ARDS); congestive heart failure;cirrhosis with ascites; sexual dysfunctions including impotence andfrigidity; and altered pulmonary function, including chronic obstructivepulmonary disease.

[0027] Accordingly, the present invention provides a compound of formulaI

[0028] or a salt thereof or a hydrate thereof

[0029] wherein

[0030] X and Y are selected independently from hydrogen and aryl, whicharyl is unsubstituted or substituted one or more times by hydroxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, aryl, heterocyclyl, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, arylC₁₋₆alkoxy, C₁₋₆alkyl,C₁₋₆alkoxy or halo, which alkyl or alkoxy groups are unsubstituted orsubstituted one or more times by halo;

[0031] m and n are independently 0 to 3, provided that m and n are notboth 0;

[0032] A represents a single bond or is —(CR_(pa) R_(pb))_(p)— wherein pis 1-3 and R_(pa) and R_(pb) are selected independently from hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy and halo, which alkyl or alkoxy groups areindependently substituted one or more times by halo;

[0033] B represents a C₄₋₈ saturated or unsaturated ring, which ring isunsubstituted or substituted one or more times by C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkenoxy, aryl, aryloxy, hydroxy, oxo, halo, amino, C₁₋₆alkylamino,di(C₁₋₆ alkyl)amino, and C₁₋₆alkylamido, which C₁₋₆alkyl or C₁₋₆alkoxygroups are unsubstituted or substituted one or more times by halo, whicharyl group is unsubstituted or substituted one or more times by aryl,heterocyclyl, aryloxy, arylC₁₋₆alkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, arylC₁₋₆alkyl, hydroxy, C₁₋₆alkenoxy, C₁₋₆alkoxy,halo, or C₁₋₆alkyl, which C₁₋₆alkyl may be substituted one or more timesby halo, and which aryl group is linked to said ring by a single bond oris benzo-condensed therewith;

[0034] subject to the proviso that the compounds on the list below(hereinafter referred to as List A) are excluded:

[0035]10-[(4-phenylpiperidin-1-yl)methyl]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene;

[0036]2-[(4-phenylpiperidin-1-yl)methyl]-6-methoxy-2-methyl-1-oxo-2H-3,4-dihydronaphthalene;

[0037]2-[(4-phenylpiperidin-1-yl)methyl]-6-methoxy-1-oxo-2H-3,4-dihydronaphthalene;

[0038]2-[(4-phenylpiperidin-1-yl)methyl]-5-methoxy-1-oxo-2H-3,4-dihydronaphthalene;

[0039]2-[(4-phenylpiperidin-1-yl)methyl]-6-ethyl-1-oxo-2H-3,4-dihydronaphthalene;

[0040]2-[(4-phenylpiperidin-1-yl)methyl]-6-benzyloxy-1-oxo-2H-3,4-dihydronaphthalene;

[0041]2-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-6-phenylethoxy-2H-3,4-dihydronaphthalene;

[0042]2-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-6-phenoxy-2H-3,4-dihydronaphthalene;

[0043]2-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-6-phenyl-2H-3,4-dihydronaphthalene;

[0044]2-[(4-phenylpiperidin-1-yl)methyl]-5-methoxy-2-methyl-1-oxo-2H-3,4-dihydronaphthalene;

[0045]2-[(4-phenylpiperidin-1-yl)methyl]-2-methyl-1-oxo-6-phenoxy-2H-3,4-dihydronaphthalene;

[0046]2-[(4-phenylpiperidin-1-yl)methyl]-2-methyl-1-oxo-6-phenyl-2H-3,4-dihydronaphthalene;

[0047]2-[(4-phenylpiperidin-1-yl)methyl]-1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphthalene;

[0048]2-[(4-phenylpiperidin-1-yl)methyl]-1-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydronaphthalene;

[0049]2-[(4-phenylpiperidin-1-yl)methyl]-1-hydroxy-6-(2-phenyl)benzyloxy-1,2,3,4-tetrahydronaphthalene;

[0050]2-[(4-phenylpiperidin-1-yl)methyl]-1-acetamido-6-methoxy-2-methyl-1,2,3,4-tetrahydronaphthalene;

[0051]2-[(4-phenylpiperidin-1-yl)methyl]-1-amino-6-methoxy-2-methyl-1,2,3,4-tetrahydronaphthalene;

[0052] 2-[(4-phenylpiperidin-1-yl)methyl]-1,2,3,4-tetrahydronaphthalene;

[0053]2-[(4-phenylpiperidin-1-yl)methyl]-7-fluoro-1,2,3,4-tetrahydronaphthalene;

[0054]3-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;

[0055]3-[(4-phenylpiperidin-1-yl)methyl]-6-fluoro-1-oxo-2H-3,4-dihydronaphthalene;

[0056]2-[(4-phenylpiperidin-1-yl)methyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene;

[0057]2-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;

[0058]2-[(4-phenylpiperidin-1-yl)methyl]-8-chloro-5-methoxy-2H-3,4-dihydronaphthalene;

[0059]2-[(4-phenylpiperidin-1-yl)methyl]-8-chloro-5-methoxy-1-oxo-2H-3,4-dihydronaphthalene,and;

[0060]2-[(4-phenylpiperidin-1-yl)methyl]-5-methoxy-1-oxo-2H-2,3-dihydroindene.

[0061] There exists a ether group of compounds of formula IA

[0062] wherein

[0063] X′, Y′, A′, B′, m′, and n′ are as defined for X, Y, A, B, m, andn respectively in formula I,

[0064] but which includes the compounds of List A.

[0065] Compounds of formula I and formula IA may exhibit stereoisomerismby virtue of the presence of chiral atoms and/or multiple bonds. Thepresent invention therefore extends to the stereoisomers of compounds offormula I, including racemates, enantiomers, diastereoisomers, andgeometrical isomers.

[0066] It has been found that, where a compound of formula I or formulaIA exhibits optical isomerism, one enantiomer possesses a greateraffinity for the ORL-1 receptor than its antipode.

[0067] Accordingly, the present invention also provides an enantiomer ofa compound of formula I.

[0068] In a further aspect, the present invention provides a mixture ofenantiomers of a compound of formula I wherein one enantiomer is presentin a greater proportion than its antipode.

[0069] As has previously been mentioned, compounds of formula I areligands of the ORL-1 receptor. Compounds of formula IA are also ligandsof the ORL-1 receptor.

[0070] Thus, there is provided a compound of formula I as an activetherapeutic substance.

[0071] According to another aspect of the present invention there isprovided a method of modulating the ORL-1 receptor activity in a humanor animal patient in need thereof, which method comprises administeringto the human or animal patient an effective amount of a compound offormula IA.

[0072] In yet another aspect of the present invention there is providedthe use of a compound of formula IA in the manufacture of a medicamentfor administration to a human or animal patient for modulating the ORL-1receptor activity.

[0073] Said compounds of formula I and formula IA may be agonists orantagonists of the ORL-1 receptor.

[0074] In accordance with a particular aspect of the present invention,an antagonist of formula I may be used as an analgesic in humans oranimals for the treatment, for example, of acute pain; chronicneuropathic or inflammatory pain, including post herpetic neuralgia,neuralgia, diabetic neuropathy and post stroke pain; osteoarthritis/backpain; and painful pregnancy labour.

[0075] In accordance with a further aspect of the invention, compoundsof formula I may be used in the treatment or prophylaxis of eatingdisorders, such as anorexia and bulimia; anxiety and stress conditions;immune system diseases; cardiovascular system dysfunctions; memory loss,cognitive disorders, motor impairment and neurodegeneration owing toAlzheimer's disease, senile dementia, Parkinson's disease or otherneurodegenerative pathologies; stroke; epilepsy; altered diuresis andsodium excretion; syndrome of inappropriate secretion of antidiuretichormone (SIADH); adult respiratory distress syndrome (ARDS); congestiveheart failure; cirrhosis with ascites; sexual dysfunctions includingimpotence and frigidity; and altered pulmonary function, includingchronic obstructive pulmonary disease.

[0076] In some embodiments, X and Y of formula I above may be selectedindependently from hydrogen and unsubstituted or substituted phenyl.

[0077] Suitably X is unsubstituted phenyl or phenyl substituted withC₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, halo, or arylC₁₋₆alkoxy.

[0078] Favourably, X is unsubstituted phenyl or phenyl substituted withmethyl, methoxy, hydroxy, fluoro, benzyloxy, bromo, or chloro.

[0079] Preferably, X is unsubstituted phenyl, or phenyl substituted withmethyl, fluoro, or chloro.

[0080] Most preferably, X is phenyl substituted with methyl.

[0081] Preferably, Y is hydrogen.

[0082] Suitably, m and n are independently 1 or 2, typically one of mand n is 1 and the other is 2.

[0083] Preferably m is 2 and n is 1.

[0084] Suitably, A is —(CR_(pa) R_(pb))_(p)— wherein p is 1-3 and R_(pa)and R_(pb) are selected independently from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy and halo, which alkyl or alkoxy groups are independentlysubstituted one or more times by halo.

[0085] Preferably A is —CH₂—.

[0086] Suitably, B represents a C₄₋₈ saturated or unsaturated ring,which ring is unsubstituted or substituted once by aryl and/or one ormore times by C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkenoxy, aryloxy, hydroxy,oxo, halo, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, andC₁₋₆alkylamido, which C₁₋₆alkyl or C₁₋₆alkoxy groups are unsubstitutedor substituted one or more times by halo, which aryl group isunsubstituted or substituted one or more times by aryl, heterocyclyl,aryloxy, arylC₁₋₆alkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,arylC₁₋₆alkyl, hydroxy, C₁₋₆alkenoxy, C₁₋₆alkoxy, halo, or C₁₋₆alkyl,which C₁₋₆alkyl may be substituted one or more times by halo, andwherein the aryl group is linked to said ring by a single bond or isbenzo-condensed therewith.

[0087] Suitably, B represents a C₄₋₈ unsaturated ring, or a C₄, C₇, orC₈ saturated ring, which ring is unsubstituted or substituted one ormore times by C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkenoxy, aryl, aryloxy,hydroxy, oxo, halo, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, andC₁₋₆alkylamido, which C₁₋₆alkyl or C₁₋₆alkoxy groups are unsubstitutedor substituted one or more times by halo, which aryl group isunsubstituted or substituted one or more times by aryl, heterocyclyl,aryloxy, arylC₁₋₆alkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,arylC₁₋₆alkyl, hydroxy, C₁₋₆alkenoxy, C₁₋₆alkoxy, halo, or C₁₋₆alkyl,which C₁₋₆alkyl may be substituted one or more times by halo, andwherein the aryl group is linked to said ring by a single bond or isbenzo-condensed therewith.

[0088] Suitably, B represents a C₄₋₈ saturated or unsaturated ring,which ring is substituted one or more times by C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkenoxy, aryl, aryloxy, hydroxy, halo, amino, C₁₋₆alkylamino,di(C₁₋₆ alkyl)amino, and C₁₋₆alkylamido, which C₁₋₆alkyl or C₁₋₆alkoxygroups are unsubstituted or substituted one or more times by halo, whicharyl group is unsubstituted or substituted one or more times by aryl,heterocyclyl, aryloxy, arylC₁₋₆alkoxy, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, arylC₁₋₆alkyl, hydroxy, C₁₋₆alkenoxy, C₁₋₆alkoxy,halo, or C₁₋₆alkyl, which C₁₋₆alkyl may be substituted one or more timesby halo, and wherein the aryl group is linked to said ring by a singlebond or is benzo-condensed therewith.

[0089] Suitably, B represents a C₄₋₈ saturated or unsaturated ring,which ring is unsubstituted or substituted one or more times byC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkenoxy, aryl, aryloxy, hydroxy, oxo, halo,amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, and C₁₋₆alkylamido, whichC₁₋₆alkyl or C₁₋₆alkoxy groups are unsubstituted or substituted one ormore times by halo, which aryl group is unsubstituted or substituted oneor more times by aryl, heterocyclyl, aryloxy, arylC₁₋₆alkoxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, arylC₁₋₆alkyl, hydroxy,C₁₋₆alkenoxy, C₁₋₆alkoxy, halo, or C₁₋₆alkyl, which C₁₋₆alkyl may besubstituted one or more times by halo, and wherein the aryl group islinked to said ring by a single bond or is benzo-condensed therewith,provided that any benzo-condensed aryl group is substituted at leastonce.

[0090] Favourably, B represents a C₆₋₇ unsaturated ring or a C₅₋₇saturated ring, which ring is unsubstituted or substituted by oxo,hydroxy, C₁₋₆alkenoxy, or C₁₋₆alkoxy, and is benzo-condensed with oneunsubstituted or substituted aryl group, wherein suitable substituentsfor said aryl group are C₁₋₆alkoxy, C₁₋₆alkyl, halo, aryl,arylC₁₋₆alkoxy, and hydroxy.

[0091] More favourably, B is cyclohexyl, cyclohexenyl, cyclopentyl,cycloheptenyl, or cycloheptyl, either unsubstituted or substituted withhydroxy, oxo, methoxy, or 2-propen-1-oxy, and is benzo-condensed witheither phenyl or naphthyl, wherein said phenyl and naphthyl groups areeither unsubstituted or substituted with methoxy, methyl, chloro,fluoro, phenyl, bromo, benzyloxy, or hydroxy.

[0092] Preferably, B is cycloheptyl either unsubstituted or substitutedwith hydroxy, or oxo, and is benzo-condensed with phenyl, said phenylgroup being either unsubstituted or substituted with methyl, chloro,fluoro, bromo, or methoxy. More preferably, B is cycloheptyl substitutedwith hydroxy, and is benzo-condensed with phenyl, said phenyl groupbeing either unsubstituted or substituted with methyl, bromo, ormethoxy.

[0093] Most preferably, B is cycloheptyl substituted with hydroxy, andis benzo-condensed with phenyl, said phenyl group being substituted withmethyl.

[0094] Thus, examples of B are 2,3-dihydroindene,1,2,3,4-tetrahydronaphthalene, 1,2-dihydronaphthalene,6,7,8,9-tetrahydro-5H-benzocycloheptene, unsubstituted or substituted byoxo, hydroxy, alkoxy, amino, dialkyamino, and/or alkylamido; orphenylcyclopentyl, phenylcyclohexyl, or phenylcycloheptyl, unsubstitutedor substituted by oxo, hydroxy, alkoxy, amino, dialkyamino, oralkylamido.

[0095] “Aryl” as used herein includes C₅₋₁₀ aryl groups, particularlyphenyl and naphthyl. C₁₋₆alkyl groups may be linear or branched and arepreferably C₁₋₂alkyl groups, more preferably methyl. “Halo” includeschloro, bromo, and fluoro groups, especially fluoro and bromo.“Heterocyclyl” as used herein includes saturated and unsaturatedheterocyclic rings.

[0096] Examples of compounds in accordance with the present inventionare:

[0097](±)-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0098](±)-7-cis-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0099] (±)-2-[(4-Phenylpiperidin-1-yl)methyl]-1,2-dihydronaphthalene;

[0100](±)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;

[0101](R)-(−)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;

[0102] (±)-2-[(4-Phenylpiperidin-1-yl)methyl]-1,2,3,4-tetrahydronaphthalene;

[0103](S)-(+)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;

[0104](±)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-hydroxy-2H-3,4-dihydronaphthalene;

[0105](±)-1,2-Dihydro-2-[(4-phenylpiperidin-1-yl)methyl]phenanthren-4-(3H)-one;

[0106] 1-(2,3-Dihydro-1H-inden-2-yl)-4-phenylpiperidine;

[0107](±)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0108](±)-3-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0109](±)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0110](±)-3-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0111](±)-cis-5-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;

[0112](±)-trans-5-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;

[0113] 2,3-Dihydro-2-[(4-phenylpiperidin-1-yl)methyl]indene;

[0114]N-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-yl)-4-phenylpiperidine;

[0115](±)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0116](±)-1,3-Dimethyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0117](±)-cis-7-[[4-(2-Methoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0118](±)-cis-3-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0119](±)-1-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0120](±)-7-[[4-(2-Hydroxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0121](±)-cis-7-[[4-(3-Fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0122](±)-cis-7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0123](±)-cis-1-Methyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0124](±)-cis-7-[[4-(4-Benzyloxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0125](±)-cis-7-[[4-(3-Bromophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0126](±)-1-Fluoro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0127](±)-7-[[4-(4-Fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0128](±)-7-[[4-(3,5-Dimethoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0129](±)-cis-1-Phenyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0130](±)-7-[[4-(2-Chlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0131](±)-cis-1-Bromo-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0132](±)-1-Benzyloxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0133](±)-cis-1-Methyl-7-[[4-(3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0134](±)-cis-1-Methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0135](±)-trans-1-Methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0136](±)-cis-1-Methoxy-7-[[4-(3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0137](±)-trans-1-Methoxy-7-[[4-(3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0138](±)-cis-1-Hydroxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0139](±)-4-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0140](±)-1,3-Dimethyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0141](±)-7-[[4-(2-Methoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0142](±)-3-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0143](±)-1-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0144](±)-7-[[4-(2-Hydroxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0145](±)-1-Methyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0146](±)-7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0147](±)-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7-dihydro-5H-benzocycloheptene;

[0148]7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;

[0149]7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;

[0150](±)-cis-5-Allyloxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;

[0151](±)-trans-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0152](±)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0153](±)-trans-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0154](+)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0155](−)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0156](+)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0157](−)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0158](+)-trans-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0159](−)-trans-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0160][4-(2-Methylphenyl)-N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)]piperidine;

[0161](−)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol,and;

[0162](+)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol.

[0163] Especially preferred compounds are:

[0164](±)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0165](±)-cis-7-[[4-(3-Fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0166](±)-cis-7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0167](±)-7-[[4-(2-Chlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0168](±)-cis-1-Bromo-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0169](±)-cis-1-Methyl-7-[[4-(3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;

[0170](−)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol,and;

[0171](−)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol.

[0172] In accordance with another aspect of the invention, there isprovided a process for the preparation of a compound in accordance withthe invention, which process comprises:

[0173] 1) where A in formula I is a bond (formula I′),

[0174] a). reacting a ketone of formula II with an amine of formula IIIunder reductive amination conditions, such as NaCNBH₃ in methanol oracetonitrile (Lane, Synthesis, 135, 1975),

[0175]  wherein B, m, n, X and Y are as defined in formula I, or

[0176] b). transforming an alcohol of formula IV into a suitable leavinggroup (e.g. methanesulfonate, p-toluenesulfonate or bromide) andsubsequent reaction with an amine of formula III,

[0177]  wherein B, m, n, X and Y are as defined in formula I; or

[0178] 2) where A in formula I is a group —(CR_(pa) R_(pb))_(p)— and pis 1 and R_(pa) and R_(pb) are both hydrogen (formula I″),

[0179] c) reacting a carboxylic acid of formula V with an amine offormula III via formation of an acyl halide or by direct reaction with acoupling agent, such as dicyclohexylcarbodiimide/1-hydroxybenzotriazole,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide/1-hydroxybenzotriazole orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate,and thereafter reducing the resulting amide of formula VI using a metalhydride or borane-based reagent,

[0180]  wherein B, m, n, X and Y are as defined in formula I, or

[0181] d) reducing a carboxylic acid of formula V to an alcohol offormula VII (Pelter Smith, Brown, Borane Reagents; Academic Press:London, 1988), and reacting said alcohol with an amine of formula IIIaccording to method b) above,

[0182]  wherein B, m, n, X and Y are as defined in formula I, or

[0183] e) oxidizing an alcohol of formula VII to an aldehyde of formulaVIII, using for example MnO₂, PDC or DMSO/oxalyl chloride (Swern, J.Org. Chem., 43, 2480, 1978) and reacting said aldehyde with an amine offormula III under reductive amination conditions, according to method a)above,

[0184]  wherein B, m, n, X and Y are as defined in formula I; or

[0185] 3) where A in formula I is a group —(CR_(pa) R_(pb))_(p)— and pis 1, R_(pa) is a C₁₋₆ alkyl group and R_(pb) is hydrogen (formula I′″),

[0186] f) reacting a carboxylic acid or a derivative thereof of formulaV with an organometallic compound of formula R_(pa)M wherein Mrepresents a metal such as Li, Mg, Cu or Zn, e.g. alkyllithiumderivatives, Grignard reagents, lithium dialkylcuprates or dialkylzincderivatives (Trost, Fleming, Comprehensive Organic Synthesis; PergamonPress: Oxford, 1991; Vol. III), and thereafter reacting the resultingcarbonylic compound IX with an amine of formula III under reductiveamination conditions, according to method a) above,

[0187]  wherein B, R_(pa), m, n, X and Y are as defined in formula I; or

[0188] 4) where A in formula I is a group —(CR_(pa) R_(pb))_(p)— and pis 1, and R_(pa) and R_(2pb) are both C₁₋₆ alkyl groups (formula I″″),

[0189] g) reacting a carbonylic compound of formula IX with anorganometallic of formula R_(pb)M, wherein M represents a metal such asLi or Mg, e.g. alkyllithium derivatives or Grignard reagents, andcoupling the resulting alcohol of formula X with an amine of formula IIIaccording to method b) above

[0190]  wherein B, R_(pa), R_(pb), m, n, X and Y are as defined informula I.

[0191] Compounds of formula II, IV and V are either known compounds ormay be prepared from known compounds with known methods (Hacksell, J.Med. Chem., 24, 429, 1981, Murthy, Tetrahedron, 38, 2831, 1982, Bowman,Tetrahedron, 48, 4027, 1992).

[0192] Compounds of formula III are either known compounds or may beprepared from known compounds with known methods (Comins, J. Org. Chem.,47, 4315, 1982).

[0193] Said compounds in accordance with the invention may be preparedin the form of salts or hydrates.

[0194] Suitable salts are pharmaceutically acceptable salts.

[0195] Suitable hydrates are pharmaceutically acceptable hydrates.

[0196] Administration of a compound in accordance with the invention maybe by way of oral, sublingual, transdermal or parenteral administration.

[0197] An effective amount of the compound of the invention will dependon factors such, for example, as the nature and severity of thedisorder(s) being treated and on the weight of the mammal. However, aunit does will normally contain 0.1 to 50 mg, for example 0.5 to 10 mg,of the compound. Unit doses will normally be administered once or morethan once a day, for example 2, 3, or 4 times a day, more usually 1 to 3times a day, such that the total daily dose is normally in the range,for a 70 kg adult of 0.1 to 50 mg, for example 0.1 to 5 mg, that is inthe range of approximately 0.001 to 1 mg/kg/day, more usually 0.005 to0.2 mg/kg/day.

[0198] For oral or parenteral administration, it is greatly preferredthat the compound is administered in the form of a unit dosecomposition, such as a unit dose oral or parenteral composition.

[0199] Such compositions are prepared by admixture and are suitablyadapted for oral or parenteral administration, and as such may be in theform of tablets, capsules, oral preparations, powders, granules,lozenges, reconstitutable powders, injectable and liquid infusiblesolutions or suspensions or suppositories.

[0200] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers, diluents, tabletting agents, lubricants,disintegrants, colourants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.

[0201] Suitable fillers include cellulose, mannitol, lactose and othersimilar agents.

[0202] Suitable disintegrants include starch, polyvinylpyrrolidone andstarch derivatives such as sodium starch glycolate.

[0203] Suitable lubricants include, for example, magnesium stearate.

[0204] Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

[0205] These solid oral compositions may be prepared by conventionalmethods of blending, filling or tabletting. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art.

[0206] Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0207] Oral formulations also include conventional sustained releaseformulations, such as tablets or granules having an enteric coating.

[0208] For parenteral administration, fluid unit dose forms may beprepared containing the compound and a sterile vehicle. The compound,depending on the vehicle and the concentration, can be either suspendedor dissolved. Parenteral solutions are normally prepared by dissolvingthe compound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition maybe frozen after filling into the vial and the water removed undervacuum.

[0209] Parenteral suspensions are prepared in substantially the samemanner except that the compound may be suspended in the vehicle insteadof being dissolved and sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent may be included in the composition to facilitate uniformdistribution of the compound of the invention.

[0210] As is common practice, the compositions will usually beaccompanied by written or printed directions for use in the treatmentconcerned.

[0211] Accordingly, in yet another aspect of the present invention thereis also provided a pharmaceutical composition comprising a compound offormula I, or a pharmaceutically acceptable salt thereof or apharmaceutically acceptable hydrate thereof, and a pharmaceuticallyacceptable carrier.

[0212] Preparation 1

[0213] (±)-4-Oxo-1,2,3,4-tetrahydro-2-naphthoic Acid

[0214] 100 mL (0.425 mol) of diethyl benzylmalonate were added dropwiseto a stirred suspension of 28 g (0.7 mol) of NaH (60% dispersion inmineral oil) in 550 mL of absolute ethanol at room temperature. Thereaction mixture was refluxed 2 h, then cooled to 50° C. and 47.1 mL(0.425 mol) of ethyl bromoacetate were added dropwise. The reactionmixture was refluxed 2 h, then quenched with 150 mL of water; a solutionof 140 g (3.5 mol) of NaOH in 400 mL of water was added and the mixturewas heated to reflux for 1 h. EtOH was removed in vacuo, the aqueoussolution was washed with Et₂O and then carefully brought to acidic pHwith 350 mL of 37% HCl and extracted with AcOEt. The solvent was removedin vacuo and the resulting residue was heated to 180° C. for 30 min.After cooling to room temperature, 100 mL of 95% H₂SO₄ were added andthe reaction mixture stirred for 2 h, then it was poured onto 500 g ofcrushed ice and extracted with Et₂O. The organic phase was dried and thesolvent removed in vacuo. The resulting residue was taken up in Et₂O,washed with 40% NaOH solution then brought to acidic pH with 37% HCl andextracted with Et₂O. The organic phase was dried and the solvent removedin vacuo. The resulting solid residue was triturated with Et₂O, filteredand dried yielding 15 g of the title compound, used without furtherpurification. m.p.=146-147° C. IR (cm⁻¹): 2924, 1692, 1600; NMR (300MHz, DMSO, δ ppm): 12.6-12.5 (bs, 1H); 7.9 (d, 1H); 7.6-7.5 (m, 1H);7.4-7.3 (m, 2H); 3.3-3.1 (m, 3H); 2.7 (m, 2H). MS (m/z): 191.1 (MH⁺).

[0215] Preparation 2

[0216] (R)-(−)-4-Oxo-1,2,3,4-tetrahydro-2-naphthoic Acid

[0217] A solution of 7.436 g (55 mmol) of (−)-α-ethylbenzylamine in 100mL of MeOH was added to a solution of 10.5 g (55 mmol) of(±)-4-oxo-1,2,3,4-tetrahydro-2-naphthoic acid in 100 mL of MeOH. Thesolvent was removed in vacuo, and the residue was dissolved in 200 mL ofAcOEt. The less soluble diastereoisomeric salt crystallised on standing.The salt was then recrystallised from AcOEt up to a constant opticalactivity, yielding 3.5 g of salt, which was transformed into the freeacid by dissolving it in 6N HCl, extracting with Et₂O and evaporatingthe solvent, yielding 2 g of the title compound. [α]²⁰ _(D)=−39.3(c=1.5, MeOH). IR, NMR and m.p. matched those of the racemate.

[0218] Preparation 3

[0219] (S)-(+)-4-Oxo-1,2,3,4-tetrahydro-2-naphthoic Acid

[0220] The mother liquors obtained from the first crystallisation ofPreparation 2 were evaporated to dryness. The residue was dissolved in6N HCl, extracted with Et₂O and evaporated to dryness, yielding 5.34 gof free acid which were treated with 3.79 g of (+)-α-ethylbenzylamineand worked up as described in Preparation 2, yielding 1.8 g of the titlecompound. [α]²⁰ _(D)=+39.48 (c=1.5, MeOH). IR, NMR and m.p. matchedthose of the racemate.

[0221] Preparation 4

[0222] 2,3-Dihydro-2-[(4-phenylpiperidin-1-yl)carbonyl]-1H-indene

[0223] 750 mg (4.6 mmol) of 2,3-dihydro-1H-inden-2-carboxylic acid(prepared as described in Hacksell, J. Med. Chem., 24, 429, 1981) weredissolved in 15 mL of CH₂Cl₂ and 0.65 mL (7.4 mmol) of oxalyl chloridewere added dropwise at 0° C. under a nitrogen atmosphere. The solutionwas allowed to warm to room temperature in 2 h, then the solvent wasremoved in vacuo. The resulting acyl chloride was dissolved in 10 mL ofCH₂Cl₂ and added to a solution of 909 mg (4.6 mmol) of4-phenylpiperidine hydrochloride and 1.9 mL (13.8 mmol) of triethylaminein 15 mL of CH₂Cl₂ at 0° C. The reaction mixture was allowed to warm toroom temperature overnight, then water was added and the organic phasewas washed with 5% HCl and dried. The solvent was removed in vacuo andthe resulting crude product was purified by flash chromatography,eluting with a mixture Et₂O/Petroleum ether 7:3, yielding 630 mg of thetitle compound. IR (cm⁻¹)=2944, 1636, 1494. NMR (300 MHz, CDCl₃, δ ppm):7.35 (m, 2H); 7.25-7.1 (m, 7H); 4.85 (m, 1H); 4.15 (m, 1H); 3.55 (m,1H); 3.4-3.3 (m, 2H); 3.3-3.1 (m, 3H); 2.85-2.6 (m, 2H); 2.0-1.9 (m,2H); 1.75.1.6 (m, 2H). MS (m/z): 306.0 (MH⁺).

[0224] Compounds of formula VI and described in Table I were obtainedfollowing the procedure described in Preparation 4. TABLE 1 VI

Prep n° Name B 5 (±)-3-[(4-Phenylpiperidin-1- yl)carbonyl]-1-oxo-2H-3,4-dihydronaphthalene

6 (S)-(+)-3-[(4- Phenylpiperidin-1-yl) carbonyl]-1-oxo-2H-3,4-dihydronaphthalene

7 (R)-(−)-3-[(4- Phenylpiperdin-1-yl) carbonyl]-1-oxo-2H-3,4-dihydronaphthalene

8 (±)-2-[(4-Phenylpiperidin-1- yl)carbonyl]-1,2,3,4-tetrahydronaphthalene

9 (±)-1,2-Dihydro-2-[(4- phenylpiperidin-1-yl) carbonyl]phenanthren-4-(3H)-one

MS Prep m.p. (m/z) n° X Y m n (° C.) IR (cm⁻¹) (MH⁺) [α]²⁰ _(D) 5 Ph H 21 118- 2934, 334.3 — 119 1688, 1642 6 Ph H 2 1 118- 2930, 334.4 +43.2120 1688, c = 1, MeOH 1642 7 Ph H 2 1 118- 2930, 334.4 −41.2 119 1688, c= 1, MeOH 1644 8 Ph H 2 1 90- 2926, 320.2 — 91 1626, 1442 9 Ph H 2 1 — —— —

[0225] Preparation 10

[0226] (±)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one-7-carboxylicAcid

[0227] A suspension of 0.7 g (3 mmol) of ethyl(±)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one-7-carboxylate (preparedas described in Bowman, Tetrahedron, 48, 4027, 1992) in 2 mL of 2N NaOH(4 mmol) was refluxed for 2 h, then cooled and extracted with Et₂O. Theaqueous layer was brought to acidic pH with 10% HCl, the precipitateformed was redissolved in Et₂O and the organic phase was washed withwater and dried. The solvent was removed in vacuo and the resultingresidue was purified by flash chromatography, eluting with a mixtureCH₂Cl₂/MeOH 9:1 respectively, yielding 0.41 g of the title compound.m.p.=134-135° C.

[0228] Preparation 11

[0229](±)-7-[(4-Phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

[0230] To a solution of 0.3 g (1.47 mmol) of(±)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one-7-carboxylic acid in 5mL of CH₂Cl₂ were added, at 0° C., 0.27 mL (3.69 mmol) of SOCl₂ and thesolution was warmed at 50° C. for 20 min. The solvent and the excessSOCl₂ were removed in vacuo and the resulting residue was redissolved in5 mL of CH₂Cl₂. 0.24 g (1.47 mmol) of 4-phenylpiperidine and 0.2 mL(1.47 mmol) of triethylamine dissolved in 5 mL of CH₂Cl₂ were added atroom temperature to this solution; the stirring was continued overnight,then the solvent was removed in vacuo and the residue was taken up inAcOEt; the organic phase was washed successively with 10% NaOH, 10% HCland water, the solvent was removed in vacuo yielding 0.49 g of the titlecompound as an oil which was used without further purification.

[0231] Preparation 12

[0232] 2-Methylphenethyl Alcohol Methanesulfonate

[0233] 10 g (0.0734 mol) of 2-methylphenethyl alcohol were dissolved in200 mL of dry CH₂Cl₂ under a nitrogen atmosphere; the solution wascooled to 5° C., 16.4 mL (0.1175 mol) of triethylamine were added,followed by a solution of 9.1 mL (0.1175 mol) of methanesulfonylchloride in 100 mL of dry CH₂Cl₂, keeping the temperature below 15° C.The reaction mixture was allowed to warm to room temperature in 2 h,then 250 mL of water were added, the organic phase was collected and thesolvent was removed in vacuo. The resulting oil was taken up in Et₂O andwashed with 1N HCl and successively with saturated NaHCO₃ solution, thesolvent was removed in vacuo, yielding 14.5 g of the title product whichwas used without further purification.

[0234] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0235] Preparation 13

[0236] Diethyl (2-methyl)phenethyl Malonate

[0237] 33.9 mL (0.223 mol) of diethyl malonate were added, under anitrogen atmosphere and at room temperature, to a solution of sodiumethoxide (prepared in situ by dissolving 2.6 g (0.0151 mol) of Na in 80mL of absolute EtOH). After 30 min, 14.5 g (0.0677 mol) of2-methylphenethyl alcohol methanesulfonate dissolved in 40 mL of abs.EtOH were added dropwise and the resulting solution was heated to refluxfor 3 h. EtOH was removed in vacuo, the residue was taken up in waterand extracted with Et₂O. The organic phase was washed successively with10% HCl and brine, dried and the solvent was removed in vacuo. Theexcess diethyl malonate was removed by distillation under reducedpressure. The resulting oil (15.6 g) was used without furtherpurification.

[0238] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0239] Preparation 14

[0240] Diethyl 2-(t-butoxycarbonylmethyl)-2-(2-methyl)phenethyl Malonate

[0241] A solution of 7.7 g (0.0277 mol) of diethyl (2-methyl)phenethylmalonate in 70 ml of dry THF were added dropwise, under a nitrogenatmosphere at room temperature, to a suspension of 1.4 g (0.036 mol) ofNaH (60% dispersion in mineral oil) in 160 mL of dry THF. The reactionmixture was stirred for 30 min, then 5.3 mL (0.036 mol) of t-butylbromoacetate were added dropwise. After 3 h the reaction mixture wasquenched with water (at 0° C.) and extracted with Et₂O. The organicphase was dried, the solvent was removed in vacuo and the residue waspurified by flash chromatography, eluting with a mixture Hexane/Et₂O8:2, yielding 9.3 g of the title compound.

[0242] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0243] Preparation 15

[0244] Diethyl 2-carboxymethyl-2-(2-methyl)phenethyl Malonate

[0245] 18.7 g (0.0476 mol) of diethyl2-(t-butoxycarbonylmethyl)-2-(2-methyl)phenethyl malonate were dissolvedin 40 mL of trifluoroacetic acid and stirred 1 h at room temperature.Trifluoroacetic acid was removed in vacuo, the residue was taken up inwater and extracted with Et₂O. The organic phase was dried and thesolvent was removed in vacuo, yielding 16.8 g of the title compoundwhich was used without further purification.

[0246] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0247] Preparation 16

[0248](±)-1-Methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicAcid

[0249] 16.8 g (0.0499 mol) of diethyl2-carboxymethyl-2-(2-methyl)phenethyl malonate were dissolved in 120 mLof CH₂Cl₂ under a nitrogen atmosphere. The solution was cooled to 5° C.and 19 mL (0.1498 mol) of oxalyl chloride were added dropwise. After 3 hthe volatiles were removed in vacuo, the resulting oil was dissolved in200 mL of CH₂Cl₂ and this solution was added dropwise, at 0° C. andunder inert atmosphere, to a suspension of 26.6 g (0.1996 mol) of AlCl₃in 300 mL of CH₂Cl₂. The resulting suspension was vigorously stirredovernight, during which time it was allowed to warm to room temperature.Water was added, followed by 1N HCl up to pH 1. The layers wereseparated, the organic phase was dried and the solvent was removed invacuo. The resulting crude product was taken up in dioxane (60 mL) and6N HCl (200 mL) and heated to reflux for 6 h. After cooling, water wasadded and the reaction mixture was extracted with Et₂O. The organicphase was dried, the solvent was removed in vacuo and the resultingcrude product was purified by flash chromatography eluting with Et₂O,yielding 5.9 g of the title product.

[0250] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0251] The following compounds were obtained according to proceduresdescribed in Preparations 12-16:

[0252](±)-1,3-Dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicacid;

[0253](±)-3-Chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicacid;

[0254](±)-1-Chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicacid;

[0255](±)-1-Fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicacid, and;

[0256](±)-1-Bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicacid.

[0257] IR, ¹H nmr spectra and mass spectra for all the above compoundswere consistent with the assigned structures.

[0258] Preparation 17

[0259](±)-1-Methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicAcid

[0260] The title compound was obtained following procedure described inPreparation 10.

[0261] IR and ¹H nmr spectra were consistent with the assignedstructure.

[0262] Preparation 18

[0263](±)-4-Methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicAcid

[0264] The title compound was obtained following procedure assigned inPreparation 10.

[0265] IR and ¹H nmr spectra were consistent with the assignedstructure.

[0266] The following compounds were obtained according to proceduredescribed in Preparation 4:

[0267](±)-1-Methyl-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0268](±)-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0269](±)-1-Methyl-7-[[4-(3-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0270](±)-1-Methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0271](±)-1-Methoxy-7-[[4-(3-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0272](±)-1,3-Dimethyl-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0273](±)-3-Chloro-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0274](±)-1-Chloro-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0275](±)-1-Fluoro-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0276](±)-1-Bromo-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0277](±)-7-[[4-(2-Methoxyphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0278](±)-7-[[4-(3-Fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0279](±)-7-[[4-(2-Methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0280](±)-7-[[4-(4-Benzyloxyphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0281](±)-7-[[4-(3-Bromophenyl)piperidin-1-yt]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0282](±)-7-[[4-(4-Fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0283](±)-7-[[4-(3,5-Dimethoxyphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0284](±)-7-[[4-(2-Chlorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;

[0285](±)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one,and;

[0286](±)-4-Methoxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.

[0287] IR, ¹H nmr spectra and mass spectra for all the above compoundswere consistent with the assigned structures.

[0288] Preparation 19

[0289](±)-1-Phenyl-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

[0290] 0.6 g (1.54 mmol) of(±)-1-bromo-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onewere dissolved in 5 mL of toluene under a nitrogen atmosphere, then 54mg (0.016 mmol) of Pd(PPh₃)₄ were added, followed by 1.5 mL of 2M Na₂CO₃solution and 225 mg (1.85 mmol) of benzeneboronic acid dissolved in 2 mLof MeOH. The resulting heterogeneous mixture was refluxed for 8 h undervigorous stirring, then after cooling it was taken up with CH₂Cl₂ andwater. 8 mL of 2M Na₂CO₃ solution and 1 mL of conc. NH₄OH were added,the organic layer was collected and dried, the solvent was removed invacuo, yielding 660 mg of the title product which was used withoutfurther purification.

[0291] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0292] Preparation 20

[0293](±)-1-Hydroxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

[0294] Under a nitrogen atmosphere, 2.2 mL (0.0234 mol) of BBr₃ wereadded to 20 mL of CH₂Cl₂, then 1.47 g (0.0039 mol) of(±)-1-methoxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onedissolved in 25 mL of CH₂Cl₂ were added dropwise at room temperature.The reaction mixture was stirred for 2 h, then it was poured onto 25 gof crushed ice, basified with conc. NH₄OH and extracted with CH₂Cl₂. Theorganic layer was dried and the solvent was removed in vacuo. Theresulting crude solid was triturated with Et₂O, filtered and dried,yielding 1.16 g of the title product.

[0295] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0296] Preparation 21

[0297](±)-1-Benzyloxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

[0298] 600 mg (0.00165 mol) of(±)-1-hydroxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onewere dissolved in 100 mL of abs. EtOH under a nitrogen atmosphere, then228 mg (0.00165 mol) of anhydrous K₂CO₃ and a catalytic amount of KIwere added, followed by 0.216 mL (0.0018 mol) of benzylbromide. Thereaction mixture was stirred 3 h at room temperature, then 0.216 mL ofbenzylbromide were added and the stirring continued overnight. Further0.216 mL of benzylbromide was added and the reaction stirred overnight.The solvent was then evaporated, the residue was taken up in water,brought to pH 1 with 1N HCl and extracted with AcOEt. The organic phasewas dried and the solvent was removed in vacuo, the resulting crudeproduct was purified by flash chromatography, eluting with a mixtureEt₂O/Hexane 8:2 respectively, yielding 595 mg of the title compound.

[0299] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

EXAMPLE 1

[0300] 2,3-Dihydro-2-[(4-phenylpiperidin-1-yl)methyl]indeneHydrochloride

[0301] 630 mg (2.06 mmol) of2,3-dihydro-2-[(4-phenylpiperidin-1-yl)carbonyl]-1H-indene dissolved in10 mL of dry THF were added dropwise to a suspension of 300 mg of LiAlH₄in 40 mL of dry THF at room temperature. The reaction mixture wasstirred 2 h, then it was quenched by sequential addition of 0.35 mL ofwater, 1 mL of 15% NaOH and 0.35 mL of water and stirred for 90 min. Theresulting precipitate was filtered by suction and the filtrate wasevaporated to dryness. The resulting residue was dissolved in THF,brought to acidic pH with Et₂O/HCl and the solvent was removed in vacuo.The resulting solid was triturated with hot acetone, filtered and dried,yielding 370 mg of the title compound. m.p.>240° C. IR (cm⁻¹)=2930,2376, 1478. NMR (300 MHz, CDCl₃, δ ppm): 7.30-7.10 (m, 1H); 3.10-3.02(m, 4H); 2.80-2.69 (m, 3H); 2.55-2.41 (m, 1H); 2.42 (d, 2H); 2.12-2.02(m, 2H); 1.86-1.78 (m, 4H). MS (m/z): 292 (MH⁺).

[0302] Compounds of formula I″ and described in Table 2 were obtainedfollowing procedure described in Example 1. TABLE 2 I″

Ex n° Name B 2 (±)-3-[(4-Phenylpiperidine- 1-yl)methyl]-1-hydroxy-2H-3,4- dihydronaphthalene

3 (±)-2-[(4-Phenylpiperidin- 1-yl)methyl]-1,2-3,4- tetrahydronaphthalenehydrochloride

MS Ex m.p. IR NMR (300 MHz) (m/z) n° X Y m n (° C.) (cm⁻¹) δ ppm (MH⁺) 2Ph H 2 1 107- 3398, (CDCl₃): 7.51(d, 1H); 322 108 2936, 7.32-7.17(m,7H); 1450 7.09(d, 1H); 5.00-4.50 (sbr, 1H); 4.79(t, 1H); 3.11(dq, 1H);2.98(dd, 1H); 2.90(dq, 1H); 2.59-2.44(m, 2H); 2.41-2.29(m, 3H);2.23-2.01(m, 3H); 1.98-1.72(m, 5H). 3 Ph H 2 1 264- 3026, (CDCl₃):12.40(sbr, 306 265 2928, 1H); 7.32-7.05(m, 1492 9H); 3.72(m, 2H);3.15-2.67(m, 11H); 2.47(m, 1H); 2.31(m, 1H); 2.00(m, 2H); 1.74-1.61(m,1H).

EXAMPLE 4

[0303](±)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthaleneHydrochloride

[0304] 1.5 g of activated MnO₂ were added to a stirred solution of 1.2 gof(±)-3-[(4-phenylpiperidin-1-yl)methyl]-1-hydroxy-2H-3,4-dihydronaphthalenein 20 mL of AcOEt. The stirring was continued for 7 days, then theresulting mixture was filtered and the filtrate evaporated to dryness.The crude product was purified by column chromatography, eluting with amixture hexane/AcOEt 9:1 respectively, yielding 0.7 g of free base whichwas dissolved in Et₂O, brought to acidic pH with Et₂O/HCl and evaporatedto dryness The resulting solid was triturated with Et₂O, filtered anddried, yielding 0.65 g of the title compound. m.p. 261-262° C. IR(cm⁻¹)=3028, 2934, 1678. NMR: (300 MHz, CDCl₃, δ ppm): 8.03 (dd, 1H);7.49 (dt, 1H); 7.33-7.18 (m, 7H); 3.12 (d, 1H); 3.03-2.92 (m, 2H); 2.86(d, 1H); 2.75 (dd, 1H); 2.55-2.30 (m, 5H); 2.16-2.02 (m, 2H); 1.84-1.76(m, 4H). MS (m/z): 320 (MH⁺)

[0305] Compounds of formula I″ and described in Table 3 were obtainedfollowing procedure described in Example 4. TABLE 3 I″

Ex n° Name B X Y 5 (R)-(−)-3-[(4- Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4- dihydronaphthalene hydrochloride

Ph H 6 (S)-(+)-3-[(4- Phenylpiperidin-1-yl) methyl]-1-oxo-2H-3,4-dihydronaphthalene hydrochloride

Ph H 7 (±)-1,2-Dihydro-2-[(4- phenylpiperidin-1-yl)methyl]phenanthren-4- (3H)-one hydrochloride

Ph H Ex m.p. IR n° m n (° C.) (cm⁻¹) 5 2 1 259- 3028, 260 2934, 1678 6 21 257- 3030, 258 2930, 1678 7 2 1 — — MS Ex NMR (300 MHz) (m/z) n° δ ppm(MH⁺) [α]²⁰ _(D) 5 (CDCl₃): 8.03(dd, 1H); 320 −11.30 7.49(dt, 1H); 7.33-c = 0.5, 7.18(m, 7H); 3.12(d, MeOH 1H); 3.03-2.92(m, 2H); 2.86(d, 1H);2.75(dd, 1H); 2.55-2.30(m, 5H); 2.16-2.02(m, 2H); 1.84- 1.76(m, 4H). 6(CDCl₃); 8.03(dd, 1H); 320 +11.74 7.49(dt, 1H); 7.33- c = 0.5, 7.18(m,7H); 3.12(d, MeOH 1H); 3.03-2.92(m, 2H); 2.86(d, 1H); 2.75(dd, 1H);2.55-2.30(m, 5H); 2.16-2.02(m, 2H); 1.84- 1.76(m, 4H). 7 — — —

EXAMPLE 8

[0306] (±)-2-[(4-Phenylpiperidin-1-yl)methyl]-1,2-dihydronaphthaleneHydrochloride

[0307] 0.5 g of(±)-3-[(4-phenylpiperidin-1-yl)methyl]-1-hydroxy-2H-3,4-dihydronaphthalenewere dehydrated with Et₂O/HCl at room temperature, yielding 0.3 g of thetitle compound. m.p.=239-240° C.; IR (cm⁻¹)=2932, 2604, 1494.NMR: (300MHz, DMSO, 353K, as a base, δ ppm): 7.30-7.02 (m, 9H); 6.46 (d, 1H);6.00 (dd, 1H); 2.89 (m, 2H); 2.65 (m, 2H); 2.40 (m, 2H); 2.10 (m, 4H);1.80-1.60 (m, 4H). MS (m/z): 304 (MH⁺).

EXAMPLE 9

[0308](±)-cis-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

[0309] 0.15 g (3.8 mmol) of LiAlH₄ were added to a solution of 0.33 g(0.95 mmol) of(±)-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onein 15 mL of dry Et₂O at 0° C. and the resulting mixture was heated toreflux overnight. After cooling, the reaction was quenched by thecareful addition of 0.5 mL of 2 N NaOH, the suspension was stirred 10min and then filtered by suction on a Celite pad washing with Et₂O. Thesolvent was removed in vacuo, yielding 0.25 g of the title compound.m.p.=48-50° C.

[0310] Compounds of formula I″ and described in Table 4 were obtainedfollowing procedure described in Example 9. TABLE 4 I″

Ex n° Name B 10 (±)-1-Methoxy-7-[(4- phenylpiperidin-1-yl)methyl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ol

11 (±)-3-Methoxy-7-[(4- phenylpiperidin-1-yl) methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol

Ex m.p. n° X Y m n (° C.) 10 Ph H 2 1 46-48 11 Ph H 2 1 45-48

EXAMPLE 12

[0311](±)-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-oneHydrochloride

[0312] 0.17 mL of the Jones reagent (prepared by mixing 2.67 g of CrO₃and 2.3 mL of conc. H₂SO₄ and adding water up to a final volume of 10mL) were added to a solution of 0.2 g (0.6 mmol) of(±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olin 13 mL of acetone. The solution was stirred at room temperature for 1h, then the solvent was removed in vacuo, the residue was taken up inwater, brought to basic pH with 10% NaOH and extracted with CH₂Cl₂. Theorganic phase was dried and the solvent was removed in vacuo, obtaining0.15 g of an oil which was dissolved in Et₂O and brought to acidic pHwith Et₂O/HCl. The resulting white solid was triturated with Et₂O,filtered and dried, yielding 0.1 g of the title compound. m.p.=220° C.(dec.).

[0313] Compounds of formula I″ and described in Table 5 were obtainedfollowing procedure described in Example 12. TABLE 5 I″

Ex. n° Name B 13 (±)-1-Methoxy-7-[(4- phenylpiperidin-1-yl)methyl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5- one hydrochloride

14 (±)-3-Methoxy-7-[(4- phenylpiperidin-1-yl) methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5- one hydrochloride

Ex. m.p. n° X Y m n (° C.) 13 Ph H 2 1 140- 143 14 Ph H 2 1 185- 188

EXAMPLE 15

[0314](±)-cis-5-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepteneHydrochloride

[0315] A solution of 0.1 g (0.3 mmol) of(±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olin 2 mL of MeOH and 0.05 mL of conc. H₂SO₄ was refluxed overnight. Aftercooling, the solvent was removed in vacuo, the residue was taken up in10% NaOH and extracted with AcOEt. The organic phase was washed withwater, dried and the solvent was removed in vacuo. The crude product waspurified by flash chromatography, eluting with a mixture CH₂Cl₂/MeOH95:5 respectively, obtaining the cis diastereoisomer as the fastereluting compound. The compound was dissolved in Et₂O and brought toacidic pH with Et₂O/HCl. The resulting white solid was triturated withEt₂O, filtered and dried, yielding 0.03 g of the title compound.m.p.=213-215° C. NMR: (300 MHz, CDCl₃, as a base, δ ppm): 7.47 (d, 1H);7.30-7.10 (m, 8H); 4.38 (d, 1H); 3.49 (s, 3H); 2.98 (m, 2H); 2.84-2.70(m, 2H); 2.53-2.41 (m, 1H); 2.30 (dd, 1H); 2.20-1.95 (m, 6H); 1.85-1.73(m, 4H); 1.20 (dd, 1H); 1.00-1.89 (m, 1H).

EXAMPLE 16

[0316](±)-trans-5-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepteneHydrochloride

[0317] The chromatography of the preceding example was continued,obtaining the trans diastereoisomer as the slower eluting compound. Thecompound was dissolved in Et₂O and brought to acidic pH with Et₂O/HCl.The resulting white solid was triturated with Et₂O, filtered and dried,yielding 0.02 g of the title compound. (m.p.=220-222° C.). NMR: (300MHz, CDCl₃, δ ppm): 7.30-7.10 (m, 9H); 4.35 (d, 1H); 3.20 (s, 3H); 3.20(d, 1H); 3.01 (m, 2H); 2.65 (m, 1H); 2.55-2.30 (m, 3H); 2.20-1.95 (m,5H); 1.80 (m, 4H); 1.31 (dt, 1H); 1.01 (dt, 1H).

EXAMPLE 17

[0318] 1-(2,3-Dihydro-1H-inden-2-yl)4-phenylpiperidine Hydrochloride

[0319] 190 mg (3 mmol) of NaCNBH₃ were added portionwise at roomtemperature to a stirred solution of 200 mg (1.5 mmol) of 2-indanone,490 mg (3 mmol) of 4-phenylpiperidine and 0.35 mL (6 mmol) of glacialacetic acid in 20 mL of MeOH. After stirring overnight, the solvent wasremoved in vacuo and the residue was taken up, in water, brought tobasic pH with 10% NaOH and extracted with AcOEt. The organic phase wasdried and the solvent removed in vacuo; the resulting crude product waspurified by flash chromatography, eluting with a mixture n-hexane/AcOEt8:2 respectively. The compound was dissolved in Et₂O and brought toacidic pH with Et₂O/HCl. The solvent was removed in vacuo and theproduct was crystallised from (i-Pr)₂O, yielding 190 mg of the titlecompound. m.p.>250° C. IR (cm−1)=2927, 2444, 1469. NMR: (300 MHz, CDCl₃,δ ppm): 7.30-7.10 (m, 9H); 3.29-3.09 (m, 5H); 2.96 (dd, 2H); 2.59-2.49(m, 1H); 2.21-2.11 (m, 2H); 1.90-1.80 (m, 4H). MS (m/z): 278 (MH⁺).

EXAMPLE 18

[0320]N-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-yl)-4-phenylpiperidineHydrochloride

[0321] The title compound was obtained according to the method describedin Example 17, starting from 3-benzosuberone (prepared as described inEwing, J. Org. Chem., 40, 2965, 1975). m.p.>250° C. IR (KBr, cm⁻¹):2940, 2466, 1455. NMR (300 MHz, CDCl₃, δ ppm): 7.32-7.19 (m, 9H);2.93-2.78 (m, 7H); 2.48-2.39 (m, 3H); 2.20-2.10 (m, 2H); 1.88-1.68 (m,4H); 1.45 (dt, 2H). MS (m/z): 306 (MH+).

EXAMPLE 19

[0322](±)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olHydrochloride

[0323] 729 mg (1.94 mmol) of(±)-1-methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onedissolved in 20 mL of dry THF were added dropwise, at 0° C. and under anitrogen atmosphere, to a suspension of 300 mg of LiAlH₄ in 15 mL of dryTHF. The reaction mixture was allowed to warm to room temperature thenheated at 60° C. for 3 h. After cooling, it was quenched by adding, at0° C., 0.3 mL H₂O, 1 mL 15% NaOH and 0.3 mL H₂O. After stirring for 1 h,the resulting precipitate was filtered by suction and the filtrate wasevaporated to dryness. The resulting residue was purified by flashchromatography, eluting with a mixture CH₂Cl₂/MeOH/conc. NH₄OH 100:3:0.3respectively, yielding 319 mg of compound, which was dissolved in Et₂O,brought to acidic pH with Et₂O/HCl and the solvent was removed in vacuo.The resulting solid was triturated with hot acetone, filtered and dried,yielding 290 mg of the title compound. m.p.>250° C. IR (KBr, cm⁻¹)=3248,2924, 1463. NMR: (300 MHz, CDCl₃, δ ppm): 7.43 (d, 1H); 7.25 (d, 1H);7.21-7.05 (m, 5H); 5.02 (d, 1H); 3.03 (dd, 1H); 3.00 (m, 2H); 2.75-2.64(m, 1H); 2.47 (dd, 1H); 2.33 (s, 6H); 2.25 (d, 1H); 2.19-2.00 (m, 4H);2.13 (s, 2H); 1.88-1.70 (m, 4H); 1.35 (m, 1H); 0.89 (m, 1H). MS (m/z):363 (M+.); 188;

[0324] Compounds of formula I″ and described in Table 6 were obtainedfollowing procedure described in Example 19. TABLE 6 I″

Ex n° Name B 20 (±)-1,3-dimethyl-7-[(4- phenylpiperidin-1-yl)methyl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-ol

21 (±)-cis-7-[[4-(2- methoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol

22 (±)-cis-3-chloro-7-[(4- phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro- 5H-benzocyclohepten-5-ol

23 (±)-1-chloro-7-[(4- phenylpiperidin-1-yl) methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

24 (±)-7-[[4-(2- hydroxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

25 (±)-cis-7-[[4-(3- fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

26 (±)-cis-7-[[4-(2- methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

27 (±)-cis-1-methyl-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol

28 (±)-cis-7-[[4-(4- benzyloxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

29 (±)-cis-7-[[4-(3- bromophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

30 (±)-1-fluoro-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol hydrochloride

31 (±)-7-[[4-(4-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

32 (±)-7-[[4-(3,5- dimethoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

33 (±)-cis-1-phenyl-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol hydrochloride

34 (±)-7-[[4-(2-chlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

35 (±)-cis-1-bromo-7-[(4- phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro- 5H-benzocyclohepten-5-ol hydrochloride

36 (±)-1-benzyloxy-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol hydrochloride

37 (±)-cis-1-methyl-7-[[4-(3- fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-olhydrochloride

38 (±)-cis-1-methoxy-7-[[4- (2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol

39 (±)-trans-1-methoxy-7-[[4- (2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol

40 (±)-cis-1-methoxy-7-[[4- (3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol

41 (±)-trans-1-methoxy-7-[[4- (3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol

42 (±)-cis-1-hydroxy-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol hydrochloride

43 (±)-4-methoxy-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol hydrochloride

Ex m.p. n° X Y m n (° C.) 20 Ph H 2 1 52-55 21 (2-OMe)Ph H 2 1 72-74 22Ph H 2 1 — 23 Ph H 2 1 — 24 (2-OH)Ph H 2 1 158- 160 25 (3-F)Ph H 2 1238- 240 26 (2-Me)Ph H 2 1 >250 27 Ph H 2 1 52-55 28 (4-OBn)Ph H 2 1225- 228 29 (3-Br)Ph H 2 1 >250 30 Ph H 2 1 218- 220 31 (4-F)Ph H 2 1227- 229 32 (3,5-di- H 2 1 223- OMe)Ph 225 33 Ph H 2 1 245- 246 34(2-Cl)Ph H 2 1 239- 240 35 Ph H 2 1 220- 224 36 Ph H 2 1 198- 202 37(3-F)Ph H 2 1 241- 243 38 (2-Me)Ph H 2 1 — 39 (2-Me)Ph H 2 1 — 40(3-F)Ph H 2 1 — 41 (3-F)Ph H 2 1 — 42 Ph H 2 1 190- 193 43 Ph H 2 1 176-189 Ex Ir MS n° (cm⁻¹) NMR (δ ppm) (m/z) 20 IR and ¹H nmr spectra wereconsistent with the assigned structure. 21 IR, ¹H nmr spectra and massspectra were consistent with the assigned structure 22 IR, ¹H nmrspectra and mass spectra were consistent with the assigned structure. 23(KBr); (200 MHz, CDCl3): 7.5(d, 1H); 7.4-7.1(m, 7H); — 3290, 5.0(d, 1H);3.6-3.4(m, 1H); 3.1-2.9(m, 2H); 2.8- 1580, 2.6(m, 3H); 2.3-1.9(m, 7H);1.9-1.7(m, 5H). 1455. 24 IR, ¹H nmr spectra and mass spectra wereconsistent with the asisgned structure. 25 (KBr); (300 MHz, CDCl₃,+D₂O + Na₂CO₃, 333 K): 353 3295, 7.49(d, 1H); 7.19-7.09(m, 2H);7.02-6.89(m, (M+.); 2925, 3H); 6.81(d, 1H); 6.75(dd, 1H); 4.82(d, 1H);192; 1588. 2.89(m, 2H); 2.75-2.60(m, 2H); 2.48(m, 2H); 149 2.48-2.34(m,1H); 2.15-1.90(m, 6H); 1.75- 1.61(m, 4H); 1.20(dt, 1H); 0.90-0.80(m,1H). 26 (KBr); (300 MHz, CDCl3): 7.59(d, 1H); 7.25-7.04(m, 349 3293;7H); 4.99(d, 1H); 3.00(dd, 2H); 2.89-2.65(m, (M+.); 2926; 3H); 2.32(s,3H); 2.27(d, 1H); 2.18-2.01(m, 6H); 188; 1454. 1.88-1.70(m, 4H);1.35(dt, 1H); 0,99(dt, 1H). 27 (KBr); (200 MHz, CDCl3): 7.5-7.0(m, 8H);5.05(d, 1H); — 3293; 3.2-2.9(m, 2H); 2.6-2.3(m, 2H; s, 3H); 2.3-1.91540; (m, 8H); 1.9-1.5(m, 7H). 1454. 28 IR, ¹H nmr spectra and massspectra were consistent with the assigned structure. 29 IR, ¹H nmrspectra and mass spectra were consistent with the assigned structure. 30(KBr); (300 MHz, CDCl3, 343K): 7.36(d, 1H); 7.31- 353 3338; 7.14(m, 6H);6.91(dd, 1H); 4.96(d, 1H); 3.39 (M+.); 2927; (ddd, 1H); 2.99(m, 2H);2.56-2.46(m, 1H); 2.40- 174; 1463. 2.21(m, 2H); 2.20-2.05(m, 6H);1.88-1.79(m, 4H); 1.39(dt, 1H); 0.98(dt, 1H). 31 (KBr); (300 MHz,CDCl3): 7.59(d, 1H); 7.30-7.12(m, 353 3269; 4H); 7.10(dd, 1H); 6.99(dd,2H); 4.98(d, 1H); (M+.); 2930; 2.99(m, 2H); 2.88-2.70(m, 2H);2.52-2.42(m, 192 1511. 1H); 2.29-1.99(m, 7H); 1.81-1.70(m, 4H); 1.38(dt, 1H); 0.99(dt, 1H). 32 IR, ¹H nmr spectra and mass spectra wereconsistent with the assigned structure. 33 IR, ¹H nmr spectra and massspectra were consistent with the assigned structure. 34 (KBr); (300 MHz,CDCl3): 7.58(d, 1H); 7.35-7.09(m, 369 3291; 7H); 4.98(d, 1H);3.07-2.85(m, 3H); 2.89-2.70 (M+.); 2928; (m, 2H); 2.30-2.03(m, 6H);1.88-1.60(m, 5H); 208; 1441. 1.38(dt, 1H); 0,99(dt, 1H). 174 35 (KBr);(300 MHz, CDCl3): 7.54(d, 1H); 7.46(d, 1H); 413 3344; 7.32-7.17(m, 5H);7.08(dd, 1H); 5.01(d, 1H); (M+.); 2937; 3.55(dd, 1H); 2.98(m, 2H);2.59(dd, 1H); 2.55- 174 1445. 2.43(m, 1H); 2.25(d, 1H); 2.13(s, 2H);2.13- 2.00(m, 4H); 1.92-1.68(m, 4H); 1.32(m, 1H), 0,90(m, 1H). 36 IR, ¹Hnmr spectra and mass spectra were consistent with the assignedstructure. 37 (KBr); (300 MHz, CDCl3): 7.42(d, 1H); 7.28-7.21(m, 3673270; 1H); 7.14(dd, 1H); 7.06(d, 1H); 7.00(d, 1H); (M+.); 2930;6.96-6.84(m, 2H); 5.40(d, 1H); 3.12(dd, 1H); 192 1440. 2.97(m, 2H);2.54-2.41(m, 2H); 2.31(s, 3H); 2.22(d, 1H); 2.19-2.00(m, 4H); 2.12(s,2H); 1.82-1.70(m, 4H); 1.31(m, 1H); 0.89(m, 1H). 38 (KBr); (200 MHz,CDCl3): 7.3-7.1(m, 6H); 6.8(m, 1H); — 3300; 5.0(d, 1H); 3.8(s, 3H);3.5(m, 1H); 3.1-2.9(m, 1540; 2H); 2.9-2.6(m, 1H); 2.35(s, 3H);2.3-1.9(m, 1463. 9H); 1.9-1.7(m, 4H); 1.35-1.2(m, 1H); 0.9(m, 1H). 39 IRand ¹H nmr spectra were consistent with the assigned structure. 40 IRand ¹H nmr spectra were consistent with the assigned structure. 41(KBr); (200 MHz, CDCl3): 7.3-6.8(m, 7H); 5.0(d, 1H); — 3295; 3.8(s, 3H);3.2(m, 1H); 2.5(m, 1H); 2.4-2.1(m, 1580; 4H); 2.1-1.6(m, 10H); 0.9(m,1H). 1455. 42 IR and ¹H nmr spectra were consistent with the assignedstructure. 43 IR and ¹H nmr spectra were consistent with the assignedstructure.

[0325] Compounds of formula I″ and described in Table 7 were obtainedfollowing procedure described in Example 12. TABLE 7 I″

Ex n° Name B 44 (±)-1,3-dimethyl-7-[(4- phenylpiperidin-1-yl)methyl]-6,7,8,9- tetrahydro-5H- benzocyclohepten-5-one hydrochloride

45 (±)-7-[[4-(2- methoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-onehydrochloride

46 (±)-3-chloro-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-one hydrochloride

47 (±)-1-chloro-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-one hydrochloride

48 (±)-7-[[4-(2- hydroxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-onehydrochloride

49 (±)-1-methyl-7-[(4- phenylpiperidin-1- yl)methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-one hydrochloride

50 (±)-7-[[4-(2- methylphenyl) piperidin-1-yl]methyl-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-one hydrochloride

Ex m.p. n° X Y m n (° C.) 44 Ph H 2 1 222- 225 45 (2-OMe)Ph H 2 1 232-234 46 Ph H 2 1 180- 185 47 Ph H 2 1 — 48 (2-OH)Ph H 2 1 216- 218 49 PhH 2 1 205- 210 50 (2-Me)Ph H 2 1 202- 205 Ex IR MS n° (cm⁻¹) NMR (δ ppm)(m/z) 44 IR and ¹H nmr spectra were consistent with the assignedstructure. 45 IR, and ¹H nmr spectra and mass spectra were consistentwith the assigned structure. 46 IR and ¹H nmr spectra were consistentwith the assigned structure. 47 IR and ¹H nmr spectra were consistentwith the assigned structure. 48 IR, and ¹H nmr spectra and mass spectrawere consistent with the assigned structure. 49 (neat, (200 MHz, CDCl₃):7.5(d, 1H); 7.4-7.1(m, 7H); — free 3.1-2.8(m, 5H); 2.65-2.5(m, 2H);2.4(s, 3H); 2.3- base): 2.25(m, 2H); 2.2-1.9(m, 4H); 1.9-1.7(m, 4H);1.7- 2900; 1.5(m, 1H). 1670; 1450. 50 IR, and ¹H nmr spectra and massspectra were consistent with the assigned structure.

EXAMPLE 51

[0326](±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7-dihydro-5H-benzocyclohepteneHydrochloride

[0327] 0.2 g (0.6 mmol) of(±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olwere dissolved in 5 mL of 1,4-dioxane and 16 mL of 37% HCl and heated toreflux for 2 h. The reaction mixture was then basified with NaOH andextracted with CH₂Cl₂. The organic phase was dried and the solvent wasremoved in vacuo. The resulting crude product was purified bychromatography, eluting with a mixture CH₂Cl₂/MeOH 100:2 respectively;The compound was dissolved in Et₂O and brought to acidic pH withEt₂O/HCl. The resulting white solid was triturated with Et₂O, filteredand dried, yielding 0.02 g of the title compound. m.p.=268-270° C.

[0328] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

EXAMPLE 52

[0329]7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepteneHydrochloride

[0330] 0.2 g of(±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7-dihydro-5H-benzocycloheptenewere dissolved in 20 mL of MeOH, added to a suspension of 100 mg of 10%Pd—C in 5 mL of MeOH and hydrogenated at 50 psi for 6 h. The catalystwas filtered off, the solvent was removed in vacuo and the resultingcrude product was purified by chromatography, eluting with a mixtureCH₂Cl₂/MeOH 100:2 respectively. The compound was dissolved in Et₂O andbrought to acidic pH with Et₂O/HCl. The resulting white solid wastriturated with Et₂O, filtered and dried, yielding 0.04 g of the titlecompound. m.p.>250° C.

[0331] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

EXAMPLE 53

[0332]7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepteneHydrochloride

[0333] The title compound was obtained as described in Examples 51 and52 starting from(±)-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol.m.p. 245° C. (dec.).

[0334] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

EXAMPLE 54

[0335](±)-cis-5-Allyloxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepteneHydrochloride

[0336] 0.2 g (0.596 mmol) of(±)-cis-7-[(4-phenylpiperdin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-oldissolved in 5 ML THF were added dropwise to a suspension of 0.029 g(0.715 mmol) of NaH (60% dispersion in mineral oil) in 10 mL THF. After30 min at room temperature, 0.12 mL of allyl bromide were added and thereaction mixture was refluxed 8 h. After cooling, the reaction mixturewas quenched by addition of MeOH and the solvent was removed in vacuo.The residue was taken up in 1 N NaOH and extracted with CH₂Cl₂; theorganic phase was dried and the solvent was removed in vacuo. Theresulting crude product was purified by chromatography, eluting with amixture CH₂Cl₂/MeOH 100:2 respectively, yielding an oil which wasdissolved in Et₂O; the solution was brought to acidic pH with Et₂O/HCland the solvent was removed in vacuo. The resulting solid was trituratedwith Et₂O, yielding 65 mg of the title product. m.p. 126-128° C.

[0337] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

EXAMPLE 55

[0338](±)-trans-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olHydrochloride

[0339] 0.7 g (2.1 mmol) of(±)-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onewere dissolved in 40 mL of MeOH and 0.35 g of NaBH₄ were addedportionwise. The reaction mixture was stirred 2 h at room temperature,the MeOH removed in vacuo, then the residue was taken up in 1N NaOH andextracted with CH₂Cl₂. The organic phase was dried and the solvent wasremoved in vacuo. The crude product was purified by chromatography,eluting with CH₂Cl₂ and then with a mixture CH₂Cl₂/MeOH 100:3respectively, yielding 100 mg of trans isomer which was dissolved in amixture CH₂Cl₂/Et₂O: The solution was brought to acidic pH with Et₂O/HCland the solvent was removed in vacuo. The resulting solid was trituratedwith hot acetone, filtered and dried, yielding 90 mg of the titlecompound. m.p.>250° C.

[0340] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

EXAMPLE 56

[0341](±)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olHydrochloride

[0342] The diastereoisomeric mixture of Example 10 (150 mg) waschromatographed on silica gel by gradient elution starting from CH₂Cl₂up to a mixture CH₂Cl₂/MeOH 100:3 respectively, to yield the cisdiastereoisomer as the faster eluting compound. The compound wasdissolved in Et₂O, the solution was brought to acidic pH with Et₂O/HCland the solvent was removed in vacuo. The resulting solid was trituratedwith hot acetone, filtered and dried, yielding 100 mg of the titlecompound. m.p. 229-231° C.

[0343] NMR (free base, 400 MHz, C₆D₆, δ ppm): 7.49 (d, 1H); 7.24-7.02(m, 6H); 6.60 (d, 1H); 4.75 (d, 1H); 3.79 (ddd, 1H); 3.41 (s, 3H); 2.75(m, 2H); 2.34 (tt, 1H); 2.20 (m, 2H); 2.02 (m, 1H); 1.93-1.63 (m, 9H);1.29 (dt, 1H); 0.84 (q br, 1H). MS (m/z): 366 (MH+); 348.

EXAMPLE 57

[0344](±)-trans-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olHydrochloride

[0345] The chromatography of the preceding example was continued,obtaining the trans diastereoisomer as the slower eluting compound. Thecompound was dissolved in Et₂O, the solution was brought to acidic pHwith Et₂O/HCl and the solvent was removed in vacuo. The resulting solidwas triturated with hot acetone, filtered and dried, yielding 40 mg ofthe title compound. m.p.>250° C.

[0346] NMR (free base, 400 MHz, C₆D₆, δ ppm): 7.21-7.03 (m, 6H); 6.88(d, 1H); 6.60 (d, 1H); 4.79 (dd, 1H); 3.40 (m, 1H); 3.38 (s, 3H); 3.22(ddd, 1H); 2.82 (m, 2H); 2.38 (m, 1H); 2.30 (m, 2H); 2.11 (m, 1H); 2.07(d, 2H); 191-1.62 (m, 6H); 1.41 (ddd, 1H); 1.18 (dt, 1H). MS (m/z): 366(MH+).

[0347] Racemic(±)-1-methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one(compound of Example 13) was separated by preparative HPLC on chiralstationary phase (Daicel Chiracel OD, elution with 90:10:0.1Hexane:Ethanol:Diethylamine, 12 mL/min), obtaining:

EXAMPLE 58

[0348](+)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-oneHydrochloride

[0349] The free base (e.e.>99% by HPLC) was dissolved in CH₂Cl₂, thesolution was brought to acidic pH with Et₂O/HCl and the solvent wasremoved in vacuo. The resulting solid was triturated with Et₂O, filteredand dried, yielding the title compound. [α]²⁰ _(D)=+27.14 (c=0.1, MeOH).NMR (free base, 300 MHz, CDCl₃, δ ppm): 7.30-7.15 (m, 7H); 7.00 (d, 1H);3.84 (s, 3H); 3.16 (ddd, 1H); 3.00-2.80 (m, 4H); 2.59 (dd, 1H);2.50-2.49 (m, 1H); 2.30 (m, 2H); 2.25-1.90 (m, 4H); 1.81-1.72 (m, 4H);1.55 (m, 1H).

EXAMPLE 59

[0350](−)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-oneHydrochloride

[0351] The free base (e.e.=96% by HPLC) was treated as described in theprevious example, yielding the title compound. [α]²⁰ _(D)=−29.14 (c=0.1,MeOH). ¹H NMR matched that of the opposite enantiomer.

[0352] Racemic(±)-cis-1-methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol(compound of Example 56) was separated by preparative HPLC on chiralstationary phase (Daicel Chiracel OD, elution with 90:10:0.1Hexane:Ethanol:Diethylamine, 12 mL/min), obtaining:

EXAMPLE 60

[0353](+)-cis-1-methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

[0354] The title compound was obtained with e.e.=98% (HPLC). [α]²⁰_(D)=+64.2 (c=0.1, EtOH/Hexane). ¹H NMR matched that of the racemate.

EXAMPLE 61

[0355](−)-cis-1-methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

[0356] The title compound was obtained with e.e.=96% (HPLC). [α]²⁰_(D)=−65.8 (c=0.1, EtOH/Hexane). ¹H NMR matched that of the racemate.

[0357] Racemic(±)-trans-1-methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol(compound of Example 57) was separated by preparative HPLC on chiralstationary phase (Daicel Chiracel OD, elution with 90:10:0.1Hexane:Ethanol:Diethylamine, 12 mL/min), obtaining:

EXAMPLE 62

[0358](+)-trans-1-methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

[0359] The title compound was obtained with e.e.>99% (HPLC). [α]²⁰_(D)=+12.7 (c=0.5, EtOH). ¹H NMR matched that of the racemate.

EXAMPLE 63

[0360](−)-trans-1-methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

[0361] The title compound was obtained with e.e.>97% (HPLC). [α]²⁰_(D)=−12.1 (c=0.5, EtOH). ¹H NMR matched that of the racemate.

EXAMPLE 64

[0362][4-(2-Methylphenyl)-N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)]piperidine

[0363] The title compound was obtained according to the method describedin Example 17.

[0364] IR, ¹H nmr spectra and mass spectra were consistent with theassigned structure.

[0365] Racemic(±)-cis-1-methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol(compound of Example 19) was separated by preparative HPLC on chiralstationary phase (Daicel Chiracel OD, elution with 90:10:0.1Hexane:Ethanol:Diethylamine, 12 mL/min), obtaining:

EXAMPLE 65

[0366](−)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

[0367] The title compound was obtained with e.e.>98% (HPLC). [α]²⁰_(D)=−49 (c=0.1, EtOH/Hexane). ¹H NMR matched that of the racemate.

EXAMPLE 66

[0368](+)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

[0369] The title compound was obtained with e.e.=92% (HPLC). [α]²⁰_(D)=+40 (c=0.1, EtOH/Hexane). ¹H NMR matched that of the racemate.

[0370] Method of Nociceptin Binding Assay

[0371] Receptor Cloning and Expression

[0372] ORL-1 receptor was stably expressed in a Chinese Hamster Ovary(CHO) cell line (ACC-317) using a pCDN vector. Subclone selection wasperformed by growth in the absence of nucleosides. The cell lineexpressing high numbers of ORL-1 binding sites was selected for furthercharacterization in radioligand binding and signal transduction assay(cAMP and GTPgS assays).

[0373] Cell Growth Conditions

[0374] CHO cells are grown in suspension, in 1017 S03 culture andmaintained at 37° C. and 5% CO₂. The cells are routinely grown on ashaker in the presence of 0.05% (v/v) pluronic acid (F68). The maximumcell density for this CHO cell lines is 4×10⁶ cells/ml. The cultures arepassed twice a week at a 1:5 or 1:10 dilution.

[0375] Membrane Preparation by Hypotonic Lysis

[0376] All steps are performed at 4° C.

[0377] 1) Harvest cells in PBS (approximately 30×10⁶ cells/tube).Collect cells by centrifugation (1200 rpm, ca 800×g 5 min).

[0378] 2) Resuspend each pellet in 10 mM dibasic phosphate buffer, pH7.2 (buffer A)—circa 30 ml/pellet. Centrifuge 15000 rpm 10 min (SorvallSS-34 rotor).

[0379] 3) Resuspend the pellets in the same volume of buffer A, incubateon ice for 20 min.

[0380]  Centrifuge at 1200 rpm, 5 min and save the supernatants.

[0381] 4) Resuspend the low speed pellets in buffer A again and repeatstep 3) two more times saving the supernatants each time.

[0382] 5) Pool the low speed supernatants. Spin (15000 rpm, 10 min) tocollect the membranes.

[0383] 6) Resuspend the pellets in buffer A containing 0.32 M sucroseand 5 mM EDTA (buffer B). Pool, spin again at high speed to concentratethe membranes and wash in this storage buffer.

[0384] 7) Resuspend in buffer B the final pellet to a finalconcentration of 5-10 mg protein/ml (ca 10×10⁶ cells/ml). Freeze thealiquots at −80° C.

[0385] Radioligand Binding

[0386] Radioligand binding experiments have been performed in Trisbuffer pH 7.4 containing 100 ug/ml Bacitracine, 4 ug/ml Leupeptine and 2ug/ml Chymostatine at the final volume of 1 ml, using [³H]-Nociceptin(Amersham, 172 Ci/mmol) as the radioligand.

[0387] Binding experiments were carried out at 25° C. for 20 min and thereaction was terminated by filtration through Whatman GF/B filterspretreated with 0.2% PEI. Filters were washed 3 times in Tris buffer pH7.4 at 4° C. The radioactivity present on the discs was measured byliquid scintillation counting using a 2500 Camberra Packard betacounter.

[0388] The most potent compounds in accordance with the presentinvention have an ORL-1 binding affinity (Ki) in the range from 1 to1000 nM.

[0389] The stereochemistry shown for the Examples in the followingSummary Table of Examples 1-66 serves to illustrate the relativestereochemistry of the compounds only.

SUMMARY TABLE OF EXAMPLES 1-66

[0390] I

Example No. X Y m n A  1 Ph H 2 1 CH₂  2 Ph H 2 1 CH₂  3 Ph H 2 1 CH₂  4Ph H 2 1 CH₂  5 Ph H 2 1 CH₂  6 Ph H 2 1 CH₂  7 Ph H 2 1 CH₂  8 Ph H 2 1CH₂  9 Ph H 2 1 CH₂ 10 Ph H 2 1 CH₂ 11 Ph H 2 1 CH₂ 12 Ph H 2 1 CH₂ 13Ph H 2 1 CH₂ 14 Ph H 2 1 CH₂ 15 Ph H 2 1 CH₂ 16 Ph H 2 1 CH₂ 17 Ph H 2 1Bond 18 Ph H 2 1 Bond 19 (2-Me)Ph H 2 1 CH₂ 20 Ph H 2 1 CH₂ 21 (2-OMe)PhH 2 1 CH₂ 22 Ph H 2 1 CH₂ 23 Ph H 2 1 CH₂ 24 (2-OH)Ph H 2 1 CH₂ 25(3-F)Ph H 2 1 CH₂ 26 (2-Me)Ph H 2 1 CH₂ 27 Ph H 2 1 CH₂ 28 (4-OBn)Ph H 21 CH₂ 29 (3-Br)Ph H 2 1 CH₂ 30 Ph H 2 1 CH₂ 31 (4-F)Ph H 2 1 CH₂ 32(3,5-di- H 2 1 CH₂ OMe)Ph 33 Ph H 2 1 CH₂ 34 (2-Cl)Ph H 2 1 CH₂ 35 Ph H2 1 CH₂ 36 Ph H 2 1 CH₂ 37 (3-F)Ph H 2 1 CH₂ 38 (2-Me)Ph H 2 1 CH₂ 39(2-Me)Ph H 2 1 CH₂ 40 (3-F)Ph H 2 1 CH₂ 41 (3-F)Ph H 2 1 CH₂ 42 Ph H 2 1CH₂ 43 Ph H 2 1 CH₂ 44 Ph H 2 1 CH₂ 45 (2-OMe)Ph H 2 1 CH₂ 46 Ph H 2 1CH₂ 47 Ph H 2 1 CH₂ 48 (2-OH)Ph H 2 1 CH₂ 49 Ph H 2 1 CH₂ 50 (2-Me)Ph H2 1 CH₂ 51 Ph H 2 1 CH₂ 52 Ph H 2 1 CH₂ 53 (2-Me)Ph H 2 1 CH₂ 54 Ph H 21 CH₂ 55 Ph H 2 1 CH₂ 56 Ph H 2 1 CH₂ 57 Ph H 2 1 CH₂ 58 Ph H 2 1 CH₂ 59Ph H 2 1 CH₂ 60 Ph H 2 1 CH₂ 61 Ph H 2 1 CH₂ 62 Ph H 2 1 CH₂ 63 Ph H 2 1CH₂ 64 (2-Me)Ph H 2 1 Bond 65 (2-Me)Ph H 2 1 CH₂ 66 (2-Me)Ph H 2 1 CH₂Example Molecular No. B Formula  1

C₂₁H₂₅NHCl  2

C₂₂H₂₇NO  3

C₂₂H₂₇NHCl  4

C₂₂H₂₅NOHCl  5

C₂₂H₂₅NOHCl  6

C₂₂H₂₅NOHCl  7

C₂₆H₂₇NOHCl  8

C₂₂H₂₅NHCl  9

C₂₃H₂₉NO 10

C₂₄H₃₁NO₂ 11

C₂₄H₃₁NO₂ 12

C₂₃H₂₇NOHCl 13

C₂₄H₂₉NO₂HCl 14

C₂₄H₂₉NO₂HCl 15

C₂₄H₃₁NOHCl 16

C₂₄H₃₁NOHCl 17

C₂₀H₂₃NHCl 18

C₂₂H₂₇N.HCl 19

C₂₅H₃₃NO.HCl 20

C₂₅H₃₃NO 21

C₂₄H₃₁NO₂ 22

C₂₃H₂₈ClNO 23

C₂₃H₂₈ClNO 24

C₂₃H₂₉NO₂.HCl 25

C₂₃H₂₈FNO.HCl 26

C₂₄H₃₁NO.HCl 27

C₂₄H₃₁NO 28

C₃₀H₃₅NO₂.HCl 29

C₂₃H₂₈BrNO.HCl 30

C₂₃H₂₈FNO.HCl 31

C₂₃H₂₈FNO.HCl 32

C₂₅H₃₃NO₃.HCl 33

C₂₉H₃₃NO.HCl 34

C₂₃H₂₈ClNO.HCl 35

C₂₃H₂₈BrNO.HCl 36

C₃₀H₃₅NO₂.HCl 37

C₂₄H₃₀FNO.HCl 38

C₂₅H₃₃NO₂ 39

C₂₅H₃₃NO₂ 40

C₂₄H₃₀FNO₂ 41

C₂₄H₃₀FNO₂ 42

C₂₃H₂₉NO₂.HCl 43

C₂₄H₃₁NO₂ 44

C₂₅H₃₁NO.HCl 45

C₂₄H₂₉NO₂HCl 46

C₂₃H₂₆ClNO.HCl 47

C₂₃H₂₆ClNO.HCl 48

C₂₃H₂₇NO₂.HCl 49

C₂₄H₂₉NO.HCl 50

C₂₄H₂₉NO 51

C₂₃H₂₇N.HCl 52

C₂₃H₂₉N.HCl 53

C₂₄H₃₁N 54

C₂₆H₃₃NO.HCl 55

C₂₃H₂₉NO.HCl 56

C₂₄H₃₁NO₂.HCl 57

C₂₄H₃₁NO₂.HCl 58

C₂₄H₂₉NO₂.HCl 59

C₂₄H₂₉NO₂.HCl 60

C₂₄H₃₁NO₂.HCl 61

C₂₄H₃₁NO₂.HCl 62

C₂₄H₃₁NO₂ 63

C₂₄H₃₁NO₂ 64

C₂₃H₂₉N 65

C₂₅H₃₃NO 66

C₂₅H₃₃NO Example No. m.p. (° C.) [α]²⁰ _(D)  1 >240 —  2 107-108 —  3264-265 —  4 261-262 —  5 259-260 −11.30 (c = 0.1, MeOH)  6 257-258+11.74 (c = 0.1, MeOH)  7 — —  8 239-240 —  9 48-50 — 10 46-48 — 1145-48 — 12 220 (dec) — 13 140-143 — 14 185-188 — 15 213-215 — 16 220-222— 17 >250 — 18 >250 19 >250 — 20 52-55 — 21 72-74 — 22 — — 23 — — 24158-160 — 25 238-240 — 26 >250 — 27 52-55 — 28 225-228 — 29 >250 — 30218-220 — 31 227-229 — 32 223-225 — 33 245-246 — 34 239-240 — 35 220-224— 36 198-202 — 37 241-243 — 38 — — 39 — — 40 — — 41 — — 42 190-193 — 43176-189 — 44 222-225 — 45 232-234 — 46 180-185 — 47 — — 48 216-218 — 49205-210 — 50 202-205 — 51 >250 — 52 >250 — 53 245 — 54 126-128 — 55 >250— 56 229-231 — 57 >250 — 58 — +27.14 (c = 0.1, MeOH) 59 — −29.14 (c =0.1, MeOH) 60 — +64.2 (c = 0.1, EtOH/Hexane) 61 — −65.8 (c = 0.1,EtOH/Hexane) 62 — +12.7 (c = 0.5, EtOH) 63 — −12.1 (c = 0.5, EtOH) 64 —— 65 — −49 (c = 0.1, EtOH/Hexane) 66 — +40 (c = 0.1, EtOH/Hexane)

1. A compound of formula I, or a salt thereof or a hydrate thereof

wherein X and Y are selected independently from hydrogen and aryl, whicharyl is unsubstituted or substituted one or more times by hydroxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, aryl, heterocyclyl, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, arylC₁₋₆alkoxy, C₁₋₆alkyl,C₁₋₆alkoxy or halo, which alkyl or alkoxy groups are unsubstituted orsubstituted one or more times by halo; m and n are independently 0 to 3,provided that m and n are not both 0; A represents a single bond or is—(CR_(pa) R_(pb))_(p)— wherein p is 1-3 and R_(pa) and R_(pb) areselected independently from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy and halo,which alkyl or alkoxy groups are independently substituted one or moretimes by halo; B represents a C₄₋₈ saturated or unsaturated ring, whichring is unsubstituted or substituted one or more times by C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkenoxy, aryl, aryloxy, hydroxy, oxo, halo, amino,C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, and C₁₋₆alkylamido, which C₁₋₆alkylor C₁₋₆alkoxy groups are unsubstituted or substituted one or more timesby halo, which aryl group is unsubstituted or substituted one or moretimes by aryl, heterocyclyl, aryloxy, arylC₁₋₆alkoxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, arylC₁₋₆alkyl, hydroxy,C₁₋₆alkenoxy, C₁₋₆alkoxy, halo, or C₁₋₆alkyl, which C₁₋₆alkyl may besubstituted one or more times by halo, and which aryl group is linked tosaid ring by a single bond or is benzo-condensed therewith; subject tothe proviso that the compounds on list A are excluded.
 2. An enantiomerof a compound of formula I according to claim
 1. 3. A mixture ofenantiomers of a compound of formula I according to claim 1 wherein oneenantiomer is present in a greater proportion than its antipode.
 4. Acompound according to claim 1 selected from:(±)-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-7-cis-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-2-[(4-Phenylpiperidin-1-yl)methyl]-1,2-dihydronaphthalene;(±)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;(R)-(−)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;(±)-2-[(4-Phenylpiperidin-1-yl)methyl]-1,2,3,4-tetrahydro naphthalene;(S)-(+)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-dihydronaphthalene;(±)-3-[(4-Phenylpiperidin-1-yl)methyl]-1-hydroxy-2H-3,4-dihydronaphthalene;(±)-1,2-Dihydro-2-[(4-phenylpiperidin-1-yl)methyl]phenanthren-4-(3H)-one;1-(2,3-Dihydro-1H-inden-2-yl)-4-phenylpiperidine;(±)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-3-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-3-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-cis-5-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;(±)-trans-5-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;2,3-Dihydro-2-[(4-phenylpiperidin-1-yl)methyl]indene;N-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-yl)-4-phenylpiperidine;(±)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-1,3-Dimethyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-7-[[4-(2-Methoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-3-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-1-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-7-[[4-(2-Hydroxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-7-[[4-(3-Fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Methyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-7-[[4-(4-Benzyloxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-7-[[4-(3-Bromophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-1-Fluoro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-7-[[4-(4-Fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-7-[[4-(3,5-Dimethoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Phenyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-7-[[4-(2-Chlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Bromo-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-1-Benzyloxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Methyl-7-[[4-(3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-trans-1-Methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Methoxy-7-[[4-(3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-trans-1-Methoxy-7-[[4-(3-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Hydroxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-4-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-1,3-Dimethyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-7-[[4-(2-Methoxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-3-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-1-Chloro-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-7-[[4-(2-Hydroxyphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-1-Methyl-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(±)-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7-dihydro-5H-benzocycloheptene;7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;7-[[4-(2-Methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;(±)-cis-5-Allyloxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocycloheptene;(±)-trans-7-[(4-Phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(±)-trans-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(+)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(−)-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;(+)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(−)-cis-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(+)-trans-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;(−)-trans-1-Methoxy-7-[(4-phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;[4-(2-Methylphenyl)-N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)]piperidine;(−)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol,and;(+)-cis-1-Methyl-7-[[4-(2-methylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol.5. A compound of formula I as defined in claim 1, for use as an activetherapeutic substance.
 6. A method of modulating the ORL-1 receptoractivity in a human or animal patient in need thereof, which methodcomprises administering to the human or animal patient an effectiveamount of a compound of formula IA

wherein X′, Y′, A′, B′, m′, and n′ are as defined for X, Y, A, B, m, andn respectively in formula I of claim 1; including the compounds of ListA.
 7. Use of a compound of formula IA as defined in claim 6 in themanufacture of a medicament for administration to a human or animalpatient for modulating the ORL-1 receptor activity.
 8. Use of anantagonist of formula I as defined in claim 1 as an analgesic in humansor animals for the treatment, for example, of acute pain; chronicneuropathic or inflammatory pain, including post herpetic neuralgia,neuralgia, diabetic neuropathy and post stroke pain; osteoarthritis/backpain; and painful pregnancy labour.
 9. Use of a compound of formula I asdefined in claim 1 in the treatment or prophylaxis of eating disorders,such as anorexia and bulimia; anxiety and stress conditions; immunesystem diseases; cardiovascular system dysfunctions; memory loss,cognitive disorders, motor impairment and neurodegeneration owing toAlzheimer's disease, senile dementia, Parkinson's disease or otherneurodegenerative pathologies; stroke; epilepsy; altered diuresis andsodium excretion; syndrome of inappropriate secretion of antidiuretichormone (SIADH); adult respiratory distress syndrome (ARDS); congestiveheart failure; cirrosis with ascites; sexual dysfunctions includingimpotence and frigidity; and altered pulmonary function, includingchronic obstructive pulmonary disease.
 10. A pharmaceutical compositioncomprising a compound of formula I as defined in claim 1, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable hydrate thereof, and a pharmaceutically acceptable carrier.11. A process for the preparation of a compound of formula I, where A informula I as defined in claim 1 is a bond (formula I′), which processcomprises: a). reacting a ketone of formula II with an amine of formulaIII under reductive amination conditions

 wherein B, m, n, X and Y are defined in accordance with formula I inclaim 1, or b). transforming an alcohol of formula IV into a suitableleaving group and subsequent reaction with an amine of formula III,

 wherein B, m, n, X and Y are defined in accordance with formula I inclaim
 1. 12. A process for the preparation of a compound of formula I,where A in formula I as defined in claim 1 is a group —(CR_(pa)R_(pb))_(p)— and p is 1 and R_(pa) and R_(pb) are both hydrogen (formulaI″), which process comprises a) reacting a carboxylic acid of formula Vwith an amine of formula III, and therafter reducing the resulting amideof formula VI,

 wherein B, m, n, X and Y are defined in accordance with formula I inclaim 1, or b) reducing a carboxylic acid of formula V to an alcohol offormula VII, and reacting said alcohol with an amine of formula III,

 wherein B, m, n, X and Y are defined in accordance with formula I inclaim 1, or c) oxidizing an alcohol of formula VII to an aldehyde offormula VIII, and reacting said aldehyde with an amine of formula IIIunder reductive amination conditions,

 wherein B, m, n, X and Y are defined in accordance with formula I inclaim
 1. 13. A process for the preparation of a compound of formula I,where A in formula I as defined in claim 1 is a group —(CR_(pa)R_(pb))_(p)— and p is 1, R_(pa) is a C₁₋₆ alkyl group and R_(pb) ishydrogen (formula I′″), which process comprises a) reacting a carboxylicacid or a derivative thereof of formula V with an organometalliccompound of formula R_(pa)M, and thereafter reacting the resultingcarbonylic compound IX with an amine of formula III under reductiveamination conditions,

 wherein B, R_(1p), m, n, X and Y are defined in accordance with formulaI in claim
 1. 14. A process for the preparation of a compound of formulaI, where A in formula I as defined in claim 1 is a group —(CR_(pa)R_(pb))_(p)— and p is 1, and R_(pa) and R_(pb) are both C₁₋₆ alkylgroups (formula I″″), which process comprises a) reacting a carbonyliccompound of formula IX with an organometallic of formula R_(pb)M, andcoupling the resulting alcohol of formula X with an amine of formula III

 wherein B, R_(pa), R_(pb), m, n, X and Y are defined in accordance withformula I in claim 1.